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Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells.雷帕霉素（everolimus）与丙草胺联用通过增强自噬作用协同诱导前列腺癌细胞凋亡。
Mol Cancer Ther. 2012 Jun;11(6):1320-31. doi: 10.1158/1535-7163.MCT-11-0954. Epub 2012 Apr 5.
2
Combination of Arsenic trioxide and Everolimus (Rad001) synergistically induces both autophagy and apoptosis in prostate cancer cells.三氧化二砷与依维莫司（RAD001）联合使用可协同诱导前列腺癌细胞发生自噬和凋亡。
Oncotarget. 2017 Feb 14;8(7):11206-11218. doi: 10.18632/oncotarget.14493.
3
The combination of RAD001 and MK-2206 exerts synergistic cytotoxic effects against PTEN mutant gastric cancer cells: involvement of MAPK-dependent autophagic, but not apoptotic cell death pathway.RAD001 与 MK-2206 联合对 PTEN 突变型胃癌细胞具有协同细胞毒性作用：涉及 MAPK 依赖性自噬，但不涉及凋亡细胞死亡途径。
PLoS One. 2014 Jan 9;9(1):e85116. doi: 10.1371/journal.pone.0085116. eCollection 2014.
4
Arsenic trioxide synergizes with everolimus (Rad001) to induce cytotoxicity of ovarian cancer cells through increased autophagy and apoptosis.三氧化二砷与依维莫司（Rad001）协同作用，通过增加自噬和凋亡诱导卵巢癌细胞的细胞毒性。
Endocr Relat Cancer. 2012 Sep 21;19(5):711-23. doi: 10.1530/ERC-12-0150. Print 2012 Oct.
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Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death.Delta-24-RGD与RAD001联合使用可通过自噬性细胞死亡诱导增强的抗胶质瘤效应。
Mol Ther. 2008 Mar;16(3):487-93. doi: 10.1038/sj.mt.6300400. Epub 2008 Feb 5.
7
mTOR inhibitor RAD001 (everolimus) induces apoptotic, not autophagic cell death, in human nasopharyngeal carcinoma cells.mTOR 抑制剂 RAD001（依维莫司）诱导人鼻咽癌细胞发生凋亡，而非自噬性细胞死亡。
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Autophagy induction with RAD001 enhances chemosensitivity and radiosensitivity through Met inhibition in papillary thyroid cancer.RAD001 诱导自噬通过抑制 MET 增强甲状腺乳头状癌细胞的化疗和放疗敏感性。
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mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review.mTOR 抑制剂在去势抵抗性前列腺癌中的应用：一项系统性评价。
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New perspectives in glioblastoma antiangiogenic therapy.胶质母细胞瘤抗血管生成治疗的新视角
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本文引用的文献

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Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors.利用癌细胞的弱点开发针对 ras 驱动肿瘤的联合疗法。
Cancer Cell. 2011 Sep 13;20(3):400-13. doi: 10.1016/j.ccr.2011.08.014.
2
PC3 is a cell line characteristic of prostatic small cell carcinoma.PC3 是一种具有前列腺小细胞癌特征的细胞系。
Prostate. 2011 Nov;71(15):1668-79. doi: 10.1002/pros.21383. Epub 2011 Mar 22.
3
Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma.使用 NVP-BEZ235 双重靶向磷酸肌醇 3-激酶和雷帕霉素哺乳动物靶蛋白作为人类卵巢癌的一种新的治疗方法。
Clin Cancer Res. 2011 Apr 15;17(8):2373-84. doi: 10.1158/1078-0432.CCR-10-2289. Epub 2011 Mar 3.
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The genomic complexity of primary human prostate cancer.原发性人类前列腺癌的基因组复杂性。
Nature. 2011 Feb 10;470(7333):214-20. doi: 10.1038/nature09744.
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Rapamycin inhibits anal carcinogenesis in two preclinical animal models.雷帕霉素抑制两种临床前动物模型中的肛门癌发生。
Cancer Prev Res (Phila). 2010 Dec;3(12):1542-51. doi: 10.1158/1940-6207.CAPR-10-0228.
6
Ductal adenocarcinoma of the prostate: increased mortality risk and decreased serum prostate specific antigen.前列腺导管腺癌：死亡率风险增加，前列腺特异性抗原降低。
J Urol. 2010 Dec;184(6):2303-7. doi: 10.1016/j.juro.2010.08.017. Epub 2010 Oct 16.
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A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model.小分子支架在原代神经元中诱导自噬，并在亨廷顿病模型中保护免受毒性影响。
Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16982-7. doi: 10.1073/pnas.1004498107. Epub 2010 Sep 10.
8
The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy.组蛋白去乙酰化酶抑制剂与 BH3 模拟物 GX15-070 的联合应用通过激活细胞凋亡和自噬发挥协同抗白血病活性。
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9
Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro.阿朴戈斯泊酮，一种新型抗凋亡 Bcl-2 家族蛋白抑制剂，能够诱导 PC-3 和 LNCaP 前列腺癌细胞发生自噬。
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10
A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum.一种天然 BH3 类似物通过调节内质网上的 Bcl-2-Beclin1 相互作用诱导抗凋亡前列腺癌细胞自噬。
Cell Death Differ. 2011 Jan;18(1):60-71. doi: 10.1038/cdd.2010.74. Epub 2010 Jun 25.

雷帕霉素（everolimus）与丙草胺联用通过增强自噬作用协同诱导前列腺癌细胞凋亡。

Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells.

机构信息

Department of Urology and Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

出版信息

Mol Cancer Ther. 2012 Jun;11(6):1320-31. doi: 10.1158/1535-7163.MCT-11-0954. Epub 2012 Apr 5.

DOI:10.1158/1535-7163.MCT-11-0954
PMID:22491797
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3374015/
Abstract

PI3K/AKT/mTOR pathway plays a key role in the tumorigenesis of many human cancers including prostate cancer. However, inhibitors of this pathway, such as Rad001, have not shown therapeutic efficacy as a single agent. Through a high-throughput screen of 5,000 widely used small molecules, we identified compounds that can synergize with Rad001 to inhibit prostate cancer cells. One of the compounds, propachlor, synergizes with Rad001 to induce apoptosis of castration-resistant prostate cancer cells via enhanced autophagy. This enhanced autophagic cell death is accompanied by increased Beclin1 expression as well as upregulation of Atg5-Atg12 conjugate and LC3-2. Rad001 and propachlor can also synergistically inhibit tumors in a xenograft animal model of prostate cancer. These findings provide a novel direction to develop combination therapies for advanced and metastatic prostate cancer that has failed the currently available therapies.

摘要

PI3K/AKT/mTOR 通路在许多人类癌症的肿瘤发生中发挥着关键作用，包括前列腺癌。然而，该通路的抑制剂，如 Rad001，作为单一药物并未显示出治疗效果。通过对 5000 种广泛使用的小分子进行高通量筛选，我们发现了一些能够与 Rad001 协同抑制前列腺癌细胞的化合物。其中一种化合物丙泊酚可通过增强自噬与 Rad001 协同诱导去势抵抗性前列腺癌细胞凋亡。这种增强的自噬细胞死亡伴随着 Beclin1 表达的增加以及 Atg5-Atg12 缀合物和 LC3-2 的上调。Rad001 和丙泊酚还可以协同抑制前列腺癌异种移植动物模型中的肿瘤。这些发现为开发针对目前可用疗法失败的晚期和转移性前列腺癌的联合治疗提供了新的方向。